Given the high mortality associated with infant HIV-1 and the fact that surrogate markers are poorly predictive of mortality risk, some experts recommend empiric highly active antiretroviral therapy (HAART) initiation in infants younger than 12 months. A problem with this approach is that it obligates infants to life-long therapy, which may be associated with cumulative drug toxicity, poor adherence, and treatment failure. Early HAART for prevention of mortality during the first 2 years of life has potential to salvage immune function and alter viral set-point, allowing withdrawal of therapy, perhaps for several years, until subsequent CD4% decline requires it. This untested approach is attractive because it combines the survival benefits of early pediatric HAART therapy with the benefits of antiretroviral deferral.

One hundred and fifty infants who initiated HAART at <13 months of age will be treated with HAART regimen for 24 months after which those who have immune reconstitution and adequate growth (~100) will be randomized to continued versus deferred therapy. Clinical outcomes, growth, and toxicity will be compared in these children to determine if interruption is a safe and beneficial strategy. Follow-up in this studies will be closely monitored by an external Data Safety and Monitoring Board (DSMB).

Growth will be compared in continuous and interrupted therapy arms at every monthly follow-up visits after randomization [ Time Frame: Over 18 months of post-randomization follow-up ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Incidence of morbidities, specifically, pneumonia, diarrhea, and hospitalization. [ Time Frame: Over 24 months of treatment with HAART and 18 months of post-randomization follow-up ] [ Designated as safety issue: No ]

After 24 months of treatment with HAART, half the eligible infants will be randomized to continued treatment with HAART for 18 months.

Drug: AZT/3TC/NVP (zidovudine/lamivudine/nevirapine)

First line HAART regimen

Drug: d4T/3TC/NVP (stavudine/lamivudine/nevirapine)

First line HAART regimen

Drug: AZT/3TC/ABC (zidovudine/lamivudine/abacavir)

First line HAART regimen

Drug: d4T/3TC/ABC (stavudine/lamivudine/abacavir)

First line HAART regimen

Drug: ddl/ABC/LPV/r (didanosine/abacavir/lopinavir-ritonavir)

Second line HAART regimen

Drug: AZT/3TC/ LPV/r (zidovudine/lamivudine/ lopinavir-ritonavir)

This first line HAART regimen will be provided to infants with prior exposure to nevirapine as part of PMTCT

Drug: - ABC/ddI or TDF/NVP or EFV (abacavir/didanosine or tenofovir/nevirapine or efavirenz)

This is a second line regimen for infants with exposure to nevirapine as part of PMTCT

Drug: ABC/3TC/NVP (abacavir/lamivudine/nevirapine)

First-line regimen

No Intervention: Interrupted HAART

After 24 months of treatment with HAART, half the eligible infants will be randomized to interrupted treatment and followed for 18 months.

Detailed Description:

Hypothesis: Deferring antiretroviral therapy in infants who have immune reconstitution and adequate growth following early therapy of primary infection (initiated HAART during primary infection at less than 13 months of age) will not compromise clinical status or growth and may spare antiretroviral toxicity.

Specific Aim/Primary Objective: To compare growth and morbidity in infants (who initiated HAART during primary infection at less than or equal to 13 months of age with subsequently normalized CD4% and growth following 24 months of HAART) randomized to deferred versus continuous therapy and followed for an additional 18 months.

Design: Randomized clinical trial involving HIV-1 treatment of infants (<13 months old) for 24 months, followed by randomization and 18 months follow-up of children randomized to continued versus deferred treatment. This trial is unblinded.

Population: HIV-1 infected infants (<13 months) newly initiating HAART and HIV-1 infected infants already receiving HAART who initiated HAART at age <13 months will be enrolled. After 24 months of treatment follow-up, children with CD4% > 25% and normalized growth will be retained in the study and randomized.

Sample size: 150 infants will be enrolled of which 100 are expected to be eligible for randomization (50 in each arm).

Treatment: All infants will be treated with HAART according to WHO and Kenyan national guidelines. The specific regimens that will be used as a part of this study are:

Caregiver of infant plans to reside in Nairobi for at least 3 years (reported by caregiver)

Caregiver is able to provide sufficient location information

B. Infants already receiving HAART

Initiated HAART at <13 months of age

Records confirming HIV positive status

Documentation of CD4% and weight prior to HAART initiation

Must be on 1st line drug regimen

Eligibility for randomization:

Completed 24 months of treatment with HAART

Normalized growth: weight for height z-score > -0.5; Child's weight must be above the 5th weight-for-age percentile and the weight curve must not be flat or falling (i.e. cross 2 major percentile lines or more over the past 3 months)

CD4% > 25

Children who recently initiated or who require anti-tuberculosis treatment at the time of randomization will be ineligible for randomization.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study.
To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.
For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00428116

Sponsors and Collaborators

University of Washington

Fred Hutchinson Cancer Research Center

University of Nairobi

Investigators

Principal Investigator:

Dalton Wamalwa, MMed, MPH

Department of Paediatrics and Child Health, Kenyatta National Hospital, University of Nairobi